CONSIDERATIONS IN DEVELOPMENT OF PEMBROLIZUMAB IN MSI-H CANCERS

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1 CONSIDERATIONS IN DEVELOPMENT OF PEMBROLIZUMAB IN MSI-H CANCERS December 2017 Christine K. Gause, Ph.D Executive Director, Biostatistics.

2 2 Microsatellite Instability-High Cancer - USPI KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

3 Biomarker Program to Identify Cancers Likely to Respond to Pembrolizumab Therapy Ligand expression on tumor Immunogenic microenvironment Increased antigen presentation due to high DNA mutation load PD-L1 Expression Immune-Related Gene Expression (GEP) Signature DNA Mismatch Repair Deficiency (MSI-H), DNA Polymerase mutation, others Goal is to identify patients most likely to benefit from treatment

4 MSI-H Cancer Has a High Mutational Burden Mismatch repair (MMR) deficiency refers to deficiency in proteins responsible for DNA MMR: MSH2, MSH6, MLH1, PMS2. MMR deficiency leads to the MSI-H phenotype. MMR deficient/msi-h cancers harbor thousands of mutations (i.e., high mutational burden; hypermutated phenotype). Microsatellite Instability DNA mutations lead to protein neo-antigens, detected as foreign & recognized by T-cells

5 Rationale and Hypothesis Hypothesis: Pembrolizumab is effective in treating any MSI- H cancer MSI-H cancer, regardless of tumor histology, is associated with a high mutational burden (hypermutated phenotype) High mutational burden leads to high neoantigen expression High neoantigen expression leads to autologous immune recognition of cancer cells By blocking PD-1 on tumor neoantigen-specific T cells, pembrolizumab can activate anti-tumor immune responses Jonathan C. Dudley et al. Clin Cancer Res 2016;22:

6 Biological Rationale for Tumor-Agnostic Approach PD-1 blockade with pembrolizumab can restore effective anti-tumor immunity in MSI-H cancer, regardless of cancer type

7 KEYNOTE (KN) 016 Investigator-Initiated Trial MSD-sponsored, investigator-initiated trial at Johns Hopkins University detection of efficacy signal in a biomarker-defined population

8 MSI-H Tumor Phenotype Associated with Efficacy in Colorectal and Non-Colorectal Patients Treated with Pembrolizumab Phase 2 Study of MK-3475 in Patients With Microsatellite Unstable (MSI) Tumors Initiated in 2013, sponsored by Johns Hopkins- Sidney Kimmel Comprehensive Cancer Center in collaboration with MSD Colorectal Cancers Cohort A Deficient in Mismatch Repair (n=40) Cohort B Proficient in Mismatch Repair (n=25) MSI-H identified by IHC (deficiency of MLH1, MSH2, MSH6, or PMS2), or by PCR (instability in 2 loci) Non-Colorectal Cancers Cohort C Deficient in Mismatch Repair (n=40) Primary endpoint: ORR Secondary endpoints: PFS by RECIST v1.1, and OS Le D et al, NEJM 2015; Diaz L et al, ASCO 2016

9 Global Phase 2 Studies KEYNOTE-164 and KEYNOTE-158: Study Design KEYNOTE-164 a /158 b (MSI-H CRC/non-CRC) Age 18 years Locally confirmed MSI-H by PCR or IHC Previously treated c ECOG PS 0-1 Measurable disease (RECIST v1.1) Life expectancy 3 months Adequate organ function Pembrolizumab 200 mg Q3W a Histologically confirmed, advanced, unresctable or metastatic CRC; previous treatment with approved therapies including fluoropyrimidine, oxaliplatin, and irinotecan. b Histologically or cytologically confirmed, advanced, incurable non-crc solid tumor; patients must have progressed on or be intolerant to standard therapies. c 2 prior therapies and 1 prior therapy for MSI-H CRC and non-crc, respectively. Clinicaltrials.gov: NCT and NCT Treated for 2 years, 35 treatments, or until PD, unacceptable AEs, or study withdrawal Survival follow-up Primary end point: ORR (RECIST v1.1, central review) Secondary end points: DOR, PFS, OS, safety

10 Ongoing Clinical Studies A Phase II Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects With Previously Treated Locally Advanced Unresectable or Metastatic (Stage IV) Mismatched Repair Deficient or Microsatellite Instability-High Colorectal Carcinoma (KEYNOTE-164) Locally confirmed MMR deficient or MSI status A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects With Advanced Solid Tumors (KEYNOTE 158) Any advanced solid tumor, with the exception of colorectal carcinoma (CRC), which is Microsatellite Instability (MSI)-High (MSI-H)

11 Overview of Trials Included in MSI-H Study Design and Patient Population Number of patients KEYNOTE-016 NCT KEYNOTE-164 NCT KEYNOTE-012 NCT KEYNOTE-028 NCT KEYNOTE-158 NCT prospective, investigator-initiated 6 sites patients with CRC and other tumors prospective international multi-center CRC retrospectively identified patients with PD-L1- positive gastric, bladder, or triple-negative breast cancer retrospectively identified patients with PD-L1- positive esophageal, biliary, breast, endometrial, or CRC prospective international multi-center enrollment of patients with MSI-H/dMMR non-crc retrospectively identified patients who were enrolled in specific rare tumor non-crc cohorts 28 CRC 30 non-crc 61 Prior therapy CRC: 2 prior regimens Non-CRC: 1 prior regimen Prior fluoropyrimidine, oxaliplatin, and irinotecan +/- anti- VEGF/EGFR mab 6 1 prior regimen 5 1 prior regimen 19 1 prior regimen 11

12 Tumor Agnostic Approach Prevalence of MSI-H prohibits conduct of randomized controlled trials by tumor type Looking for a consistent, durable treatment effect which supports utility of pembrolizumab across multiple tumor types Primary efficacy endpoint across trials: ORR Key secondary efficacy endpoint: Duration of response Analysis approach: Pooled across all trials and across all tumor types to examine consistency of effect 12

13 Pooled ORR Results for Patients with MSI-H/dMMR Cancer N=149 Objective response rate ORR (95% CI) 39.6% (31.7, 47.9) Complete response rate 7.4% Partial response rate 32.2% Response duration Median in months (range) NR (1.6+, 22.7+) % with duration 6 months 78% Source: USPI 13

14 Pooled DOR Results for Patients with MSI-H/dMMR Cancer Median DOR (mos): Not reached ( ) Number (KM %) responders 6 mos: 46 (78%) Confirmed responses are durable 14

15 Results by Tumor Type for Patients with MSI-H/dMMR Cancer Objective response rate DOR range N n (%) 95% CI (months) CRC (36%) (26%, 46%) (1.6+, 22.7+) Non-CRC (46%) (33%, 59%) (1.9+, 22.1+) Endometrial cancer 14 5 (36%) (13%, 65%) (4.2+, 17.3+) Biliary cancer 11 3 (27%) (6%, 61%) (11.6+, 19.6+) Gastric or GE junction cancer 9 5 (56%) (21%, 86%) (5.8+, 22.1+) Pancreatic cancer 6 5 (83%) (36%, 100%) (2.6+, 9.2+) Small intestinal cancer 8 3 (38%) (9%, 76%) (1.9+, 9.1+) CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable. Source: USPI 15

16 Results by Tumor Type for Patients with MSI-H/dMMR Cancer (continued) Non-CRC (continued) Breast cancer Prostate cancer Bladder cancer Esophageal cancer Sarcoma Thyroid cancer Retroperitoneal adenocarcinoma Small cell lung cancer Renal cell cancer Objective response rate DOR range N n (%) 95% CI (months) (46%) (33%, 59%) (1.9+, 22.1+) 2 PR, PR (7.6, 15.9) 2 PR, SD NE 1 PR PD 1 NE 1 PR CR PD CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable. Source: USPI 16

17 Pembrolizumab Addresses Unmet Need in MSI-H/dMMR Cancer Population MSI-H cancer represents a unique, biomarker-identified disease with a common immunobiology MSI-H cancers are readily identifiable using locally available assays (e.g., PCR, IHC) The low prevalence of the MSI-H phenotype in uncommon or rare cancers preclude RCTs for individual types of MSI-H cancers Pembrolizumab addresses an unmet medical need with a favorable benefit risk profile in previously treated patients with advanced MSI-H cancer

18 Conclusions There is a strong biological rationale for anti-pd-1 pembrolizumab therapy of MSI cancer, regardless of tumor histology Clinical trials have demonstrated durable clinical efficacy of pembrolizumab for the treatment of MSI-H colorectal and non-colorectal cancer Challenges in drug development for a tumor-agnostic indications Study design for providing evidence of clinical efficacy - Low prevalence of biomarker in uncommon or rare cancers may prevent conduct of RCTs for individual tumor types defined by biomarker in a timely manner Identification of study population

19 THANK YOU 19